(1) Field of the Invention
The present invention relates to treatment of animals with dihydroxyquinoline compounds, and more particularly to such treatment by application of such compounds to the feed of the animal.
(2) Description of the Prior Art
Animals that have been shipped, particularly over long distances, or deprived of food and/or water for a period of time commonly suffer stress, which often leads to a variety of afflictions. For example, calves often react poorly to their shipment to feed yards. In fact, usually most calves are sick when they arrive at the feed yard, suffering from a disease or other manner of ill-health. Typically the condition of the cattle is referred to as bovine respiratory disease (BRD). Because of their ill-health, upon arrival at the feed yard, the calves are placed into a pen, typically for about 45 to about 60 days, so that they may be segregated from the healthy cattle in the feed yard and nursed back to full health. Such newly arrived, segregated calves are termed "receiving cattle."
Due to the stress of shipment, receiving cattle tend to shrink during the shipment and perhaps 85% are sick when they arrive at the feedlot, or become sick, particularly with respiratory disease, soon after arrival. The receiving cattle tend to drink large quantities of water, but often tend not to get up and eat. Many require medication such as vaccines. Some even fail to recover from the sickness induced by the shipping stress, which sometimes results in death of calves. Thus, shipping produces undesirable stress and morbidity in the calves and contributes to higher medical costs and other costs associated with delays in return to health, loss of useable cattle due to disease and death, and reduced rate of weight gain and feed efficiency in the feed yard (i.e., weight gain per pound of feed). Accordingly, a treatment or other technique for accelerating restoration to health, increasing rate of weight gain, and reducing morbidity of the receiving cattle, and for reducing medical costs and improving feed efficiency would be highly desirable. In sum, the morbid cattle tend to require greater medical expense, to grow slower throughout the feedlot phase, are less efficient in converting feed to weight gain, and their carcasses tend to be graded lower after slaughter. Other ruminant mammals, such as sheep, suffer similarly from stress.
In addition, many meat products derived from ruminant mammals (such as, cattle and sheep), swine and fish have very limited shelf lives. After a relatively short period of time, the meat may turn color and become rancid (that is, develop an unacceptable smell or flavor or both). In short, it spoils. Shelf life for beef is typically measured as the length of time for the meat, in plastic trays, overwrapped with an oxygen-permeable polyvinyl chloride film, and displayed under fluorescent lighting (150 foot candles) at 4.degree. C., to discolor; to turn brown or grey. This definition will be used herein to apply to other meat products as well.
By this measure, shelf life for beef, even if sealed from exposure to air, is about seven days from slaughter, after which it may turn from red to brown or grey and spoil. And, as limited as this shelf life is, because of shipping delays, less than ideal storage conditions and increased surface area resulting from cutting the meat into steaks, the typical marketable life of steak in the display case is substantially shorter--closer to twelve hours. Moreover, while the quality and freshness of steak or other meat is commonly evaluated by the color of the meat, color is not a reliable indicator of quality or freshness. Meat can turn brown or grey significantly prior to spoilage. Thus, large quantities of high quality, fresh meat becomes unmarketable and thus is wasted because of deceptively premature color change.
The resulting food waste and loss from spoilage associated with shelf life limitations amounts to billions of dollars in the U.S. alone. In fact, it has been estimated that increasing shelf life of beef in the supermarket by just two days could save the U.S. beef industry up to $175 million through increased beef sales. See Schaefer et al., Proc. Holstein Beef Prod. Symposium (1991), p. 175. The total value to the U.S. beef industry of increasing the shelf life of beef by just one to two days has been estimated at $1 billion. Hill, Ga. Stocker-Finnisher Conference (1992).
Thus, many efforts have been made toward increasing the shelf life of beef. Often the efforts have involved direct treatment of the beef, for example, with preservatives.
Other efforts, however, have been directed to treatment of the cattle themselves, such as supplementing their diets with chemical additives. With respect to cattle treatment by dietary intervention, research from the Universities of Wisconsin and Georgia indicates that adding 1200 to 1300 IU Vitamin E daily (100 ppm alpha-tocopherol acetate in the feed) to the diet of feedlot cattle extends the shelf life of several cuts of beef from a maximum of about seven days to about fourteen days or more. Williams et al., California Nutrition Conference (1993), pp. 23-42. It is believed that the Vitamin E increases the shelf life of beef--that is, maintains the meat color--by retarding the aging process by which metmyoglobin gradually replaces the red oxymyoglobin, causing the meat to become brown. However, the cost of this Vitamin E supplement is about 1.5 cents per animal a day, or $2.50 additional cost per animal. Because this cost is not recovered directly by the producer, it can be prohibitive. Nevertheless, completely satisfactory alternative dietary supplements are unknown. In fact, dietary techniques face long odds of success, at least in part with respect to ruminant mammals because many dietary ingredients are extensively destroyed during passage through the rumen. Even measurements with various commercial sources of Vitamin E indicated that intestinal availability was only 36 to 52% of that being fed. Shin and Owens, OK. State Univ. Animal Research Report, 154-158 (1990). Because shelf life extenders are so beneficial and alternatives are so limited, the use of Vitamin E is increasing dramatically despite its cost.
Although the addition of 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (commonly referred to as "ethoxyquin") to animal feeds as a dietary supplement to improve the shelf life of food products derived from animals consuming the feeds or to improve the health of stressed animals has nowhere even been suggested in the current art, its use as a feed ingredient for various reasons is well known. For example, because ethoxyquin is an antioxidant, it has been added to certain animal feeds to preserve the feed itself; that is, to prevent the feed constituents from spoiling. See, for example, U.S. Pat. Nos. 5,066,498 and 5,000,964, both to McCauley, III, which teach the use of up to 1.5% Santoquin.RTM. (an ethoxyquin composition sold by Solutia Inc.) to prevent oxidation and breakdown of certain components of a horse feed composition designed for treatment of the horse's hooves and coat. However, it is not clear that this use in feeds has resulted in ingestion of the ethoxyquin by the animals. It is reported in the background section of U.S. Pat. No. 4,986,996 to Barlow et al., that although ethoxyquin has been widely approved for use in animal feed and is the most commonly used anti-oxidant in fish meal intended for that use, within hours of the addition of the ethoxyquin to the feed, analyses of the feed no longer detect any trace of ethoxyquin. On the other hand, when ethoxyquin is ingested, tissue levels of ethoxyquin have been found to be similar whether calves had developed their rumen or not. deMille et al., Can. J. Anim. Sci. 52:351-361 (1972). Thus, even though many dietary ingredients are extensively destroyed during passage through the rumen, research to date suggests that ethoxyquin is not completely destroyed in the rumen. Indeed, it has been reported that addition of ethoxyquin to diets of dairy cattle has resulted in the appearance of ethoxyquin in the fat of the resulting milk. Dunkley et al., Supplementing Rations with Tocopherol and Ethoxyquin to Increase Oxidative Stability of Milk, J. Dairy Sci., Vol. 50, No. 4, pp. 492-499 (1967); Dunkley et al., Compounds in Milk Accompanying Feeding of Ethoxyquin, J. Dairy Sci., Vol. 51, No. 8, pp. 1215-1218 (1968).
Ethoxyquin also has been reported to have been used in a concentration of 0.05 to 0.1% (500-1,000 ppm) in a feed composition for breeding cattle with N3 fatty acid-accumulated beef. See Canadian Patent No. 2,087,792. According to page 10 of that Canadian patent, the ethoxyquin is used as an anti-oxidant and "also plays an anti-oxidation activity in the cattle's body, as well as in the feed composition, to prevent the oxidative decomposition of N3 fatty acid in spoilage of feed during long-term storage." And, in U.K., Pat. No. 144,024, the possible candidacy of ethoxyquin as an anti-oxidant component of a food or feed supplement to prevent the occurrence of or to retard cancer is reported. It is suggested there that the ethoxyquin concentration should be sufficient for the daily consumption to be about 0.01 to 500 mg.
Dietary ethoxyquin also has been applied to animals other than cattle. For example, it has been reported to reduce or to prevent certain maladies associated with a deficiency of Vitamin E, in particular, encephalomalacia, exudative diathesis in chicks, muscular dystrophy in chicks and lambs and fetal resorption in rats. It is unclear whether these effects have been direct effects on the target tissues or indirect effects through preventing lipid oxidation and reducing Vitamin E usage or by preventing Vitamin E destruction in the diet or the gut. Miller and White, Nutr. Rep. Int. 12:245-252 (1975); Whanger et al., Nutr. Rep. Inst. 13:159-173 (1976). However, dietary ethoxyquin has been reported to prevent lipid oxidation in muscle tissues in broilers and layers. Bartov and Bornstein, Br. Poultry Sci. 18:59-68 (1977); Combs and Regenstein, Poultry Sci. 59:347-351 (1980). The ethoxyquin concentration in the feed in the broiler study was 75 to 150 ppm by weight, and 150 ppm of ethoxyquin was found to be as effective as about 15 ppm alpha-tocopherol acetate. In the layer study, the ethoxyquin concentration was 500 ppm. Ethoxyquin was detected in the muscle tissue of poultry and lambs, suggesting that the effect is directly in the tissue. deMille et al., Can. J. Anim. Sci. 52:351-361 (1972).
Despite these reports of uses of ethoxyquin in feed, there is no indication that the ethoxyquin has had any effect on the shelf life of meat products derived from the animals or on the health of receiving cattle. In fact, ethoxyquin has been reported to be a direct food additive, but even that has been for purposes other than to increase shelf life of the food or to improve the health of stressed animals. For example, U.S. Pat. No. 4,079,153 to Coleman, U.S. Pat. No. 4,087,561 to Bharucha and Coleman and U.S. Pat. No. 4,088,793 to Bharucha, Rubin and Cross disclose methods for reducing formation of nitrosamines by applying ethoxyquin directly to the meat.
Thus, the livestock industry and particularly the cattle industry, is still searching not only for ways to improve the health of receiving cattle, but also for inexpensive and simple techniques for extending the shelf life of animal-derived food products, such as beef and milk.
Moreover, it is noteworthy that these industries encounter several other problems as well and if a further benefit of the cattle health and shelf life treatments is to alleviate some of these problems as well, the value of the treatment would be enhanced even more. Among these problems may be noted the offensive odor associated with animal waste (e.g., cattle and swine manure). In addition, cattle and sheep, in particular, have been afflicted with high rates of liver abscesses. Commercially, about 15-30% of livers from feedlot cattle are discarded, primarily due to presence of abscesses. Thus, a method that reduces the incidence of liver abscesses or lessens their severity also would be beneficial. In fact, it has been reported that in a small study 2,000 ppm ethoxyquin appeared to increase rate of liver regeneration in rats by 26 to 34%. See Gavino et al., Life Sci. 36:1771-1777 (1985). Also, meat from younger animals is typically more desirable than that from older animals. Therefore, a technique that can delay the maturity of an animal or at least the apparent maturity, would be desirable as well. In addition, a certain percentage of beef is dark in color initially and therefore becomes unmarketable regardless of its age. As a result, that percentage is simply waste. Thus, methods for reducing the incident of dark color beef would be desired as well. Finally, of course, faster and more efficient weight gain rates are always desirable.